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Abstract
More than 1 out of 10 women worldwide are diagnosed with polycystic ovary syndrome
(PCOS), the leading cause of female reproductive and metabolic dysfunction. Despite
its high prevalence, PCOS and its accompanying morbidities are likely underdiagnosed,
averaging > 2 years and 3 physicians before women are diagnosed. Although it has been
intensively researched, the underlying cause(s) of PCOS have yet to be defined. In
order to understand PCOS pathophysiology, its developmental origins, and how to predict
and prevent PCOS onset, there is an urgent need for safe and effective markers and
treatments. In this review, we detail which animal models are more suitable for contributing
to our understanding of the etiology and pathophysiology of PCOS. We summarize and
highlight advantages and limitations of hormonal or genetic manipulation of animal
models, as well as of naturally occurring PCOS-like females.
Study Question: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? Summary Answer: International evidence-based guidelines including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. What Is Known Already: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. Study Design, Size, Duration: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. Participants/Materials, Setting, Methods: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis, and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. Main Results and the Role of Chance: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; ii) reducing unnecessary testing; iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. Limitations, Reasons for Caution: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. Wider Implications of the Findings: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. Study Funding/Competing Interest(S): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREEII criteria and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC
Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.
Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries1, and is often accompanied by insulin resistance2. The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity3,4. This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility. Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype. This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.
[1
]
Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden
[2
]
Departments of Pediatrics, Obstetrics and Gynecology, and Environmental Health Sciences,
University of Michigan , Ann Arbor, Michigan
[3
]
Fertility & Research Centre, School of Women’s and Children’s Health, University of
New South Wales , Sydney, New South Wales, Australia
[4
]
Centre for Neuroendocrinology and Department of Physiology, School of Biomedical Sciences,
University of Otago , Dunedin, New Zealand
[5
]
Department of Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
[6
]
School of Health Sciences and Education, University of Skövde , Skövde, Sweden
[7
]
University of Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition , F-59000 Lille, France
[8
]
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University
of California , California
[9
]
Department of Obstetrics and Gynecology, Wisconsin National Primate Research Center,
University of Wisconsin , Madison, Wisconsin
Author notes
Correspondence: Elisabet Stener-Victorin, Department of Physiology and Pharmacology, Karolinska Institutet,
Stockholm, Sweden. E-mail:
elisabet.stener-victorin@
123456ki.se
and David H Abbott, Department of Obstetrics and Gynecology, Wisconsin National Primate
Research Center, Madison, WI. E-mail:
abbott@
123456primate.wisc.edu
This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (
http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium,
provided the original work is properly cited.
History
Date
received
: 30
October
2019
Date
accepted
: 14
April
2020
Date: 08
June
2020
Page count
Pages: 39
Funding
Funded by: Swedish Medical Research Council, DOI 10.13039/501100006310;
Award ID: 2018-02435
Funded by: Novo Nordisk Foundation, DOI 10.13039/501100009708;
Award ID: NNF19OC0056647
Funded by: Stockholm County Council and Karolinska Institutet;
Funded by: National Institutes of Health, DOI 10.13039/100000002;
Award ID: HD041098
Award ID: HD044232
Award ID: P50HD071836
Award ID: HD044405
Award ID: HD028934
Award ID: OD011106
Award ID: DK121559
Funded by: European Research Council, DOI 10.13039/501100000781;
Award ID: ERC-2016-CoG
Award ID: 725149/REPRODAMH
Funded by: National Health and Medical Research Council, DOI 10.13039/501100000925;
Award ID: APP1022648
Award ID: APP1158540
Funded by: Health Research Council of New Zealand, DOI 10.13039/501100001505;
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